July 5, 2018
Antibiotic overuse and misuse has led to the
spread of antibiotic resistance, a serious pubic health issue that means
previously treatable bacterial infections have now become potentially deadly.
Yet while we already know that some drug combinations can help to fight
multidrug-resistant (MDR) infections, the wider potential use of drug
combinations has remained largely unexplored, and they are rarely used in the
clinic.
In
what they claim is the first large-scale screening study of its kind,
scientists at the European Molecular Biology Laboratory (EMBL) in Germany
teamed up with researchers in Germany, France, Switzerland, the U.K., and the
U.S. to profile the effects of almost 3000 drug combinations - including
antibiotics and food additives - on laboratory strains of three MDR bacterial
species.
The
results highlighted a number of synergistic combinations that were also
effective against clinical isolates of MDR bacteria in vitro, as
well as in an in vivo insect model. In one of the most
effective pairings, a common food additive improved the effectiveness of an
antibiotic that is now rarely used because of bacterial resistance against it.
Reporting
in Nature, the researchers, headed by the EMBL’s Nassos Typas,
Ph.D., say that as well as identifying novel drug combinations that could
undergo further testing, their results provide new insights into drug–drug
interactions and provide a framework for investigating whether the same
interactions occur across different species and between individuals.
“For
antibacterial drug therapies, our study shows that non-antibiotic drugs hold
promise as adjuvants, offers a new path for narrow spectrum therapies and
identifies effective synergies against MDR clinical isolates,” they write in
their paper entitled “Species-Specific Activity of Antibacterial Drug
Combinations.”
To
try and derive the general principles behind drug–drug interactions, the researchers
probed the effects of the 3000 drug combinations against each of six laboratory
strains of three Gram-negative pathogens, Escherichia coli, Salmonella
enterica serovar Typhimurium, and Pseudomonas aeruginosa,
which all belong to the highest-risk group for antibiotic resistance.
Fifty-nine percent of the drugs were antibiotics, 23% were other human-targeted
drugs and food additives, “most of which have reported antibacterial and/or
adjuvant activity,” the team notes, while 18% were other compounds that have
known bacterial targets.
Results
from the screen suggested that of all the interactions identified, about 500
drug combinations improved antibiotic outcome. However, there were 50% more
antagonistic, than synergistic interactions. There were also clear patterns,
the authors report. “Notably, antagonisms and synergies exhibited a clear
dichotomy in our data,” the team writes. “Antagonistic interactions occurred
almost exclusively between drugs that target different cellular processes,
whereas synergies were also abundant for drugs of the same class or that target
the same process.”
Antagonism
can be explained by interactions occurring at the drug target level, as the two
inhibitors might effectively help the cell to buffer different processes that are
disrupted, but the researchers also found that in many cases antagonism
occurred because of the effects of one drug decreasing the intracellular
concentration of the othe compound.
In
contrast with the finding that antagonistic interactions tended to impact on
different cellular processes, the team found that synergies often occurred
between drugs that targeted the same cellular processes, across all of the
three bacterial species. They suggest that while synergism can result when two
different drugs attack different parts of the same cellular process, it may
also result when the combination impacts, this time positively, on
intracellular drug concentrations.
Interestingly,
about 80% of the drug–drug interactions were highly conserved within species,
yet 13% to 32% were strain specific. And 70% of interactions occurred in only
one species, with just 5% occurring showing conservation across all three
species, despite the fact that the three bacterial species chosen are
relatively closely related. This finding suggests that it may be possible to
develop drug combinations that act on specific species, the authors suggest.
“Such specificities can be beneficial for creating narrow-spectrum therapies
with low collateral damage, by using synergies that are specific to pathogens
and antagonisms that are specific to abundant commensals.”
The
researchers then tested pairs of drugs that had demonstrated seven of the
strongest and most conserved synergistic interactions, against six MDR isolates
from human patients. The drug combinations comprised antibiotics,
human-targeted drugs, or food additives. Encouragingly, all seven combinations
acted synergistically in most of the strains tested, and in some cases
combinations of food additives and antibiotics were effective against clinical
isolates, even when the additive has no antibacterial activity on its own.
“This synergy underlines the importance of exploring the role of food additives
in combinatorial therapies,” the authors write.
The
strongest synergistic pairing against clinical MDR isolates was that of
vanillin, a food additive that gives vanilla its characteristic flavor, and
spectinomycin, an antibiotic that has historically been used to treat
gonorrhea, but which is now only rarely used because of widespread resistance.
"Of the combinations tested, this was one of the most effective and
promising synergies we identified," says Ana Rita Brochado, Ph.D., first
author on the paper and research scientist at EMBL. Subsequent tests confirmed
that vanillin boosted the antibacterial effect of spectinomycin against E.
coli MDR isolates, but antagonized many other drugs, including other
antibiotics in the same class as spectinomycin.
While
the obvious focus is on identifying combinations that boost the effects of
antibiotics, in some instances, dampening antibiotic effects can also be
beneficial, Dr. Typas suggests. “Antibiotics can lead to collateral damage and
side effects because they target healthy bacteria as well. But the effects of
these drug combinations are highly selective, and often only affect a few
bacterial species. In the future, we could use drug combinations to selectively
prevent the harmful effects of antibiotics on healthy bacteria. This would also
decrease antibiotic resistance development, as healthy bacteria would not be
put under pressure to evolve antibiotic resistance, which can later be
transferred to dangerous bacteria."
The
authors acknowledge that further preclinical studies in different species will
be required before it is possible to think about translating the findings into
the clinic. Even so, they point out, the large scale of the study provided new
insights into the general principles behind drug–drug interactions, which could
help the more rational selection of drug pairs in the future. The findings
could also offer a basis for carrying similar screens in other microbes. “Some
of the principles that we have identified probably go beyond anti-infectives
and microbes.”
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